Microfluidic devices and methods of manufacturing

ABSTRACT

Microfluidic devices and associated methods of manufacturing are disclosed herein. In one embodiment, a method for method for producing a microfluidic device includes forming a target structural pattern on a substrate, the substrate having a polymeric substrate material with a solubility parameter. The method also includes selecting a bonding solvent based on a difference between the solubility parameter of the polymeric substrate material and a solubility parameter of the bonding solvent. The method further includes bonding the substrate having the target structural pattern with a cover using the selected bonding solvent.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application claims priority to U.S. Provisional Application No. 61/584,532, filed on Jan. 9, 2012.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This work was supported in part by the National Science Foundation (CTS-0626471) and the National Institute of Health (NCRR1R21RR023146-01A2). The government has certain rights in this work.

BACKGROUND

The field of microfluidics has recently drawn attention from many academic areas, such as sample concentration, continuous separation, chemical sensing, cell processing, genomics, metabolomics, and drug discovery. Microfluidics generally deals with behaviors, control, and manipulation of fluids that are geometrically constrained to a small scale (e.g., sub-millimeter).

However, affordable, reliable, and flexible microfluidic fabrication techniques are not readily available. Conventional techniques typically utilize glass and silicon because such materials may be readily processed using traditional microelectronics fabrication techniques. Glass and silicon also have high chemical resistance and well-characterized surface properties. However, drawbacks of such fabrication techniques include high cost, low throughput, device fragility, limitations on structure geometry, and poor sealing efficiencies. Polymers are promising alternatives to glass and silicon for being inexpensive, flexible in substrate selection, and easy to mass produce. For example, polydimethylsiloxane (PDMS) has been used in microfluidic fabrications with soft-lithography and oxygen plasma bonding techniques. However, PDMS channels delaminate at pressures above about 100 psi and are easily deformed at lower pressures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1K are schematic diagrams illustrating a process of manufacturing a microfluidic device in accordance with embodiments of the present technology.

FIG. 2 shows example scanning electron microscope (“SEM”) images of various molds during pattern transfer and the imprinted channel in a poly(methyl methacrylate) (PMMA) plate.

FIG. 3 shows example SEM images of cross-sections of bonded channels produced during a bonding experiment.

DETAILED DESCRIPTION

Various embodiments of microfluidic devices and associated methods of manufacturing are described below. The term “microfluidic” is used throughout to refer to a feature having a hydraulic perimeter less than 1 millimeter. A person skilled in the relevant art will also understand that the technology may have additional embodiments, and that the technology may be practiced without several of the details of the embodiments described below with reference to FIGS. 1A-3.

As discussed above, affordable, reliable, and flexible microfluidic fabrication techniques are not readily available. The inventor has recognized that bottlenecks in microfluidic fabrication include difficulties in imprinting a target pattern onto a polymeric substrate and securely bonding a microfluidic component with a protective cover. In response, several embodiments of the present technology provide an efficient and cost-effective method of forming a target pattern on a polymeric substrate.

Fabrication of polymeric microfluidic devices can include mold fabrication, replication of structures, and bonding. Metal wires, micro-machined silicon stamps, and metal molds have been used to imprint hard plastics. Silicon molds have also been used to transfer patterns by electroforming. These techniques, however, have their respective drawbacks. For example, silicon molds are fragile during hot embossing, and metal molds are expensive. As used herein, “hot-embossing” generally refers to a pattern imprinting process to transfer a pattern from a mold to a target material when the target material is softened by increasing temperature above a glass transition temperature of the target material.

In response, polymeric molds have been developed to imprint a desired pattern on a polymeric substrate. A polymeric mold typically includes a polymeric mold material attached to a backing material (e.g., glass or silicon). For example, a suitable mold material can include a negative photoresist with a highly cross-linked structure upon UV light exposure, high mechanical strength, good thermal stability and chemical resistance. However, due to incompatible thermal expansion and poor adhesion between the polymeric mold material and the backing material, such polymeric molds can only last a limited number of times during hot embossing.

FIGS. 1A-1K are cross-sectional diagrams illustrating an example process performed during experiments for manufacturing a microfluidic device that at least partially overcomes the foregoing difficulties of manufacturing microfluidic devices. Though particular process operations are shown for illustration purposes in FIGS. 1A-1K, other embodiments of the process may include additional and/or different operations than those discussed below. Devices manufactured according to several embodiments of the process exhibit a lower surface roughness than those produced with reactive ion etched or wet etched silicon molds.

In the discussion below, a list of materials is given for convenience and illustration. However a wide range of plastics, solvents and substrate materials, such as those listed in Table 1, may be used when performing the same steps to produce the same final result. As such, the list of materials presented herein is non-limiting and illustrative for the purposes of general explanation only. Additionally, while specific temperatures, pressures, solvents and lengths of time are described in the disclosure, the information below should be not be read as limiting to the applicability of additional pressures, temperatures, solvents and lengths of time for materials included in the broader disclosure but not discussed with similar specificity.

Plexiglas G-UVT PMMA was obtained from Arkema (Philadelphia, Pa.). This acrylic sheet can transmit over 80% ultraviolet (UV) light down to 285 nm in wavelength, without obvious UV transmission loss or yellowing after more than 7,000 hours of severe UVB weathering. SU-8 photoresist and developer were obtained from Microchem (Newton, Mass.). Glass plates (3×3″) were obtained from Sargent-Welch (Buffalo, N.Y.). Methylcellulose (400 cP viscosity of 2% aqueous solution at 25° C.), ethanolamine and barium hydroxide were purchased from Sigma (St. Louis, Mo.). Fluorescent proteins, r-phycoerythrin (PE) and green fluorescent protein (GFP) were obtained from Invitrogen (Eugene, Oreg.) and Millipore (Billerica, Mass.), respectively. PDMS (Sylgard 184) kit including base and curing agent were obtained from Dow Corning (Midland, Mich.). (3-trimethoxysilylpropyl)diethylenetriamine was obtained from Gelest inc. (Morrisville, Pa.). Tridecafluoro-1,1,2,2-tetradydrooctyl-trichlorosilane was from United Chemical Technologies Inc. (Bristol, Pa.). Hydrochloric acid was purchased from Fisher Scientific (Fair Lawn, N.J.). Concentrated sulfuric acid, 30% hydrogen peroxide and isopropanol (IPA) were obtained from Mallinckrodt Baker Inc. (Phillipsburg, N.J.).

As an initial operation of the process, a carrier substrate 100 may be prepared, as shown in FIG. 1A. In the illustrated example, glass plates were used as carrier substrate and were initially flushed with deionized water, dried with compressed air, and placed in a piranha solution (3:1 volume ratio of concentrated sulfuric acid to 30% hydrogen peroxide) for 30 min to remove any residual organic dust on the surfaces. After rinsing with water, the glass plates were dried and a monolayer of aminosilane was grown on the glass plates. In other examples, the carrier substrates can also include a silicon, polymeric, metal, ceramic, and/or other suitable types of substrate and prepared according to other suitable techniques

As shown in FIG. 1B, the process can include depositing (e.g., by spin coating, screen printing, etc.) a photoresist 102 (e.g., a negative photoresist (SU-8 2000)) onto the carrier substrate 100 (e.g., a pre-treated glass plate). In the illustrated example, a SU-8 film on the glass plates was soft-baked at 95° C. and slowly cooled to room temperature. As shown in FIG. 1C, the carrier substrate 100 with the spin coated photoresist 102 was covered with a photomask 104 and exposed to radiation (e.g., UV light) to transfer a pattern of desired features. After exposure, a portion of the photoresist 102 was removed, as shown in FIG. 1D. In the illustrated example, the carrier substrate 100 with the deposited photoresist 102 was post-baked at 65° C. and 95° C., respectively, and then developed in the SU-8 developer with the help of ultrasonic energy. The resulting component is referred to as a SU-8/glass hybrid mold. Different thicknesses of the photoresist may require different soft bake time, UV exposure dose, post exposure time, and developing time.

As shown in FIG. 1E, a first polymeric mold 106 (e.g., a PDMS mold) was formed based on the pattern of the photoresist 102 on the carrier substrate 100. In the illustrated example, PDMS base and a curing agent were mixed at a 10:1 weight ratio. The mixed pre-polymer was degassed in a vacuum for 30 minutes, poured against the SU-8/glass hybrid mold, and cured at 80° C. for one hour. The cured PDMS was then peeled off from the SU-8/glass hybrid mold, which results in a PDMS mold, as shown in FIG. 1F.

The process then includes forming a second polymeric mold (e.g., with a photoresist material and/or other suitable materials) based on the first polymeric mold. In the illustrated example, a sufficient amount of SU-8 2100 was poured into a plastic beaker and placed in a vacuum oven at 120° C. for 5 hours to remove its solvent. After solvent evaporation, the oven was vented to atmospheric pressure to form a SU-8 melt. The PDMS mold was put into the oven. SU-8 melt was cast on the PDMS mold and allowed to cool down to room temperature in the oven. As shown in FIG. 1G, the SU-8 melt was flood-exposed to UV light with a dose of 7.2 J/cm² and post-baked at 95° C. and then hard baked at 150° C. in the oven. Finally, the cross-linked SU-8 mold was removed from the PDMS mold to form the second polymeric mold 108, as shown in FIG. 1H.

As shown in FIG. 1I, the process then includes embossing the structural features of the second polymeric mold 108 to a polymeric substrate 110 (e.g., a PMMA plate) to form microfluidic channels 112 and/or other suitable features. Photos of example channels 112 are shown in FIG. 3. In the illustrated example, the cross-linked SU-8 mold was hot embossed into a 0.118 in.-thick Plexiglas G-UVT clear PMMA plate. The SU-8 mold and a PMMA plate were sandwiched between two 3 mm-thick glass plates that were then sandwiched with a 0.5″ thick aluminum block on each side. The assembly was put into a 140° C. convection oven for approximately 30 min to soften the PMMA plate. After 10 min, the assembly was taken out of the oven and cooled down to approximately 70° C. for about 15 minutes. The PMMA plate was then removed from the SU-8 mold, and as shown in FIG. 1J.

The process may then include drilling holes (not shown) at suitable positions relative to channels 112 on the embossed PMMA plate. The process may then include attaching a cover 114 to the embossed polymeric substrate 110, as shown in FIG. 1K. In the illustrated example, a blank Plexiglas PMMA plate was used as the cover plate to seal channels 112. A layer of IPA was placed on the top surfaces of the cover plate to be bonded. The embossed PMMA plate was placed on the spread IPA with the bonding side facing towards the IPA. The two PMMA plates were sandwiched between two glass plates and then between two aluminum blocks. The assembly was immersed in a 70° C. IPA bath for 5 minutes. The assembly was taken out of the IPA bath and allowed to cool down to room temperature.

The bonding system was disassembled to release the bonded PMMA plates (referred herein as a “chip”). In certain embodiments, the process can optionally include removing residual solvent to restore transparency and/or annealing to attenuate internal stresses that resulted from bonding. For example, in the illustrated example, the chip was put in a 70° C. oven for one hour to evaporate IPA and then in a 100° C. oven for another hour. In other embodiments, the foregoing operations may be omitted.

Even though an SU-8 mold was formed as an example of the second polymeric mold 106, in other embodiments, the second polymeric mold 106 can also include a hybrid mold (e.g., constructed from both an epoxy and a glass). For example, in in one instance, the PDMS mold may be peeled off from the SU-8/glass hybrid mold. The PDMS mold may be placed on a center of a cover plate to enclose the channel. A low-viscosity adhesive may be used to fill the channel between the PDMS mold and the cover plate. The adhesive-filled assembly is placed in an oven for 4 hours at 120° C. followed by 2 hours at 175° C. After the adhesive is hardened, the PDMS mold is peeled off and may be used again. The epoxy/glass hybrid mold may be used to emboss the polymeric substrate 110, as shown in FIG. 1I.

FIG. 2 shows SEM images of different molds during transfer and the imprinted channel in the PMMA plate. In particular, photo (a) shows the SU-8/glass hybrid mold; photo (b) shows the PDMS mold; photo (c) shows the SU-8 mold; and photo (d) shows the embossed PMMA plate. In the particular example, the initial SU-8/glass mold has a 40 μm high by 80 μm wide SU-8 single straight line on a glass plate. It can be seen that feature fidelity between molds is well maintained. There was little obvious deformation observed on the SU-8 mold after it was used ten times.

Referring back to FIGS. 1A-1K, in the embodiments of the process discussed above, the bonding of the polymeric substrate 110 and the cover 114 relies on inter-molecular diffusion. Ordinary thermal bonding may be implemented around the glass transition temperature of PMMA to enhance this diffusion. However, because the body of the polymeric substrate 110 might be softened at the glass transition temperature, significant alteration of channel features may occur. On the other hand, solvent-assisted thermal bonding tends to improve inter-molecular diffusion only at the interfaces. Therefore, several embodiments of the process also include controlling solubility of the polymeric substrate in a bonding solvent as described below.

Without being bound by theory, for dissolution of a polymer into a solvent, the process is thermodynamically determined by a free energy change of mixing as follows:

ΔG=ΔH−TΔS

where ΔG is a change in Gibbs free energy, ΔH is a change in enthalpy, T is an absolute temperature, and ΔS is a change in entropy on mixing. When the free energy change is negative, the dissolving process is believed to be thermodynamically favorable. Solubility parameters or Hildebrand parameters, δ, describe the enthalpy change of simple liquids and polymers. For a binary regular solution, the enthalpy change is given as

ΔH=(δ₁−δ₂)²φ₁φ₂ V

where δ₁ and φ₁ are a solubility parameter and a volume fraction of component 1, respectively, δ₂ and φ₂ are a solubility parameter and a volume fraction of component 2, respectively, and Vis the volume of the mixture.

The solubility parameters provide a measure of molecular attraction of a substance and may be used to predict solubility of a polymer in a solvent. It is believed that, in certain embodiments, two components are soluble if their solubility parameters differ by less than about 1.0 (cal/cm³)^(0.5). Therefore, suitable solvents for PMMA (9.3 (cal/cm³)^(0.5)) can include toluene (8.9 (cal/cm³)^(0.5)), benzene (9.2 (cal/cm³)^(0.5)), chloroform (9.3 (cal/cm³)^(0.5)), tetrahydrofuran (THF, 9.3 (cal/cm³)^(0.5)), methyl chloride (9.7 (cal/cm³)^(0.5)), ethylene dichloride (9.8 (cal/cm³)^(0.5)), and isopropanol (IPA, δ=11.5 (cal/cm³)^(0.5)). Other example solvents for various polymeric materials are listed in the table below. In other embodiments, the solvent may be selected to have their solubility parameters differ by less than about 0.9 (cal/cm³)^(0.5), about 0.7 (cal/cm³)^(0.5), about 0.5 (cal/cm³)^(0.5), and/or other suitable values.

Solubility Plastics Parameter bonding solvent PMMA 9.3 Isopropanol, n-butanol, cyclohexanol Polystyrene (PS) 9.1 Isopropanol, n-butanol, cyclohexanol Polycarbonate (PC) 9.8 Dimethylformamide, ethanol, 1- propanol, n-octane, diethyl ether, n-heptane Cyclo-olefin copolymer 6.6 Cyclohexane, ethylactate, (COC) diacetone alcohol, 1,2- dichloropropane, carbon tetrachloride, xylene, toluene

As a result, the bonding solvent may be selected to have a target difference in solubility parameters such that dissolution of the polymeric substrate 110 occurs only at a thin layer (e.g., 10 microns) on the surface. Once a bonding solvent is chosen, the process also includes controlling a bonding temperature based on the free energy change of solution. As a result, strong bonding may be achieved without damage to integrity of the channels 112 and without using a sacrificial material in the channels 112. Even though the cover 114 is discussed above with reference to FIG. 1K as having the same material as the polymeric substrate 110, in other embodiments, the cover may be constructed from a cover material different than the polymeric substrate 110. As a result, the cover material may have a solubility parameter different than that of the polymeric substrate 110. In such embodiments, the bonding solvent may be selected to have a target difference in solubility parameters based on the solubility parameter of the polymeric substrate 110, the solubility parameter of the cover material, or a combination thereof.

FIG. 3 shows some cross-sections of bonded channels produced during a bonding experiment with various SU-8 molds. The sizes of the channels are as follows: (a) 40×80 μm; (b) 50×280 μm; (c) 10×1000 μm; (d) 20×120 μm. It was observed that the shape of the sealed channel was very close to the imprinted channel. Several embodiments of the bonding process discussed above can also seal shallow channels. In FIG. 4( c), a 10 μm high by 1000 μm wide channel was sealed at a height/width aspect ratio of 0.01.

From the foregoing, it will be appreciated that specific embodiments of the disclosure have been described herein for purposes of illustration, but that various modifications may be made without deviating from the disclosure. For example, instead of using PMMA as the polymeric substrate, polycarbonate (PC), cyclic olefin copolymers (COC), polystyrene (PS), and/or other suitable polymeric materials may also be used. In addition, many of the elements of one embodiment may be combined with other embodiments in addition to or in lieu of the elements of the other embodiments. Accordingly, the technology is not limited except as by the appended claims. 

I/We claim:
 1. A method for producing a microfluidic device, comprising: depositing a photoresist material onto a carrier substrate; patterning the deposited photoresist material to have a target pattern on the carrier substrate; transferring the target pattern from the carrier substrate to a first mold of a first polymeric material; forming a second mold of a second polymeric material with the first polymeric mold, the second mold having a mold pattern corresponding to the target pattern, wherein the second polymeric material is different than the first polymeric material; and imprinting a substrate with the mold pattern using the second mold, the substrate having a polymeric substrate material.
 2. The method of claim 1 further comprising bonding the imprinted substrate with a cover using a solvent, the cover having the same polymeric substrate material.
 3. The method of claim 2, further comprising removing residual solvent to increase transparency after bonding the imprinted substrate with the cover.
 4. The method of claim 1 wherein the polymeric substrate material includes poly(methyl methacrylate), and the method further includes bonding the imprinted substrate with a cover using a solvent selected from the group consisting of isopropanol, n-butanol, and cyclohexanol.
 5. The method of claim 1 wherein the polymeric substrate material includes polystyrene, and the method further includes bonding the imprinted substrate with a cover using a solvent selected from the group consisting of isopropanol, n-butanol, cyclohexanol.
 6. The method of claim 1 wherein the polymeric substrate material includes polycarbonate, and the method further includes bonding the imprinted substrate with a cover using a solvent selected from the group consisting of dimethylformamide, ethanol, diethyl ether, n-heptane.
 7. The method of claim 1 wherein the polymeric substrate material includes cyclo-olefin copolymer, and the method further includes bonding the imprinted substrate with a cover using a solvent selected from the group consisting of cyclohexane, ethylactate, diacetone alcohol, 1,2 dichloropropane, carbon tetrachloride, xylene, and toluene.
 8. A method for method for producing a microfluidic device, comprising: forming a target structural pattern on a substrate, the substrate having a polymeric substrate material with a solubility parameter; selecting a bonding solvent based on a difference between the solubility parameter of the polymeric substrate material and a solubility parameter of the bonding solvent; and bonding the substrate having the target structural pattern with a cover using the selected bonding solvent.
 9. The method of claim 8 wherein selecting the bonding solvent includes: determining a difference between the solubility parameter of the polymeric substrate material and a solubility parameter of a candidate solvent; and if the determined difference is less than about 1.0 (cal/cm³)^(0.5), selecting the candidate solvent as the bonding solvent.
 10. The method of claim 8 wherein selecting the bonding solvent includes: determining a difference between the solubility parameter of the polymeric substrate material and a solubility parameter of a candidate solvent; and based on the determined difference, predicting solubility of the polymeric substrate material in the candidate solvent.
 11. The method of claim 8 wherein selecting the bonding solvent includes: calculating an enthalpy change as follows: ΔH=(δ₁−δ₂)²φ₁φ₂ V where δ₁ and φ₁ are a solubility parameter and a volume fraction of component 1, respectively, δ₂ and φ₂ are a solubility parameter and a volume fraction of component 2, respectively, and V is a mixture volume of the candidate solvent and the polymeric substrate material; and calculating a free energy change of mixing as follows: ΔG=ΔH−TΔS where ΔG is a change in Gibbs free energy, ΔH is a change in enthalpy, T is an absolute temperature, and ΔS is a change in entropy on mixing; and predicting solubility of the polymeric substrate material in the candidate solvent based on the calculated free energy change.
 12. The method of claim 8 wherein bonding the substrate includes bonding the substrate having the target structural pattern with the cover using the selected bonding solvent without protecting the target structural pattern with a sacrificial material.
 13. The method of claim 8 wherein bonding the substrate includes: bonding the substrate having the target structural pattern with the cover using the selected bonding solvent without protecting the target structural pattern with a sacrificial material; and fastening the cover to the substrate with the formed bond generally without damage to the target structural pattern on the substrate.
 14. The method of claim 8 wherein: the polymeric substrate material includes poly(methyl methacrylate) having a solubility parameter of about 9.3 (cal/cm³)^(0.5); and selecting the bonding solvent includes selecting a solvent with a solubility parameter greater than about 8.3 (cal/cm³)^(0.5) and lower than about 11.6 (cal/cm³)^(0.5).
 15. The method of claim 8 wherein bonding the substrate includes bonding the substrate having the target structural pattern with a cover using the selected bonding solvent, the cover having the same polymeric substrate material as the substrate.
 16. A method for method for producing a microfluidic device, comprising: forming a target structural pattern on a substrate, the substrate having a polymeric substrate material; bonding the substrate having the target structural pattern with a cover using a bonding solvent at a bonding temperature, wherein a difference in solubility parameter between the polymeric substrate material and the bonding solvent is lower than about 1.0 (cal/cm³)^(0.5); and controlling the bonding temperature based on a free energy change corresponding to the polymeric substrate material dissolving in the bonding solvent.
 17. The method of claim 16 wherein controlling the bonding temperature includes: calculating an enthalpy change as follows: ΔH=(δ₁−δ₂)²φ₁φ₂ V where δ₁ and φ₁ are a solubility parameter and a volume fraction of component 1, respectively, δ₂ and φ₂ are a solubility parameter and a volume fraction of component 2, respectively, and V is a mixture volume of the candidate solvent and the polymeric substrate material; with the calculated enthalpy change, calculating a free energy change of mixing as follows: ΔG=ΔH−TΔS where ΔG is a change in Gibbs free energy, ΔH is a change in enthalpy, T is an absolute temperature, and ΔS is a change in entropy on mixing; and controlling the bonding temperature based on the calculated Gibbs free energy.
 18. The method of claim 16 wherein controlling the bonding temperature includes selecting a bonding temperature such that the target structural pattern on the substrate is generally not damaged during bonding.
 19. The method of claim 16 wherein bonding the substrate includes bonding the substrate with the cover without using a sacrificial material on the substrate, and wherein controlling the bonding temperature includes selecting a bonding temperature such that the target structural pattern on the substrate is generally not damaged during bonding.
 20. The method of claim 16 wherein controlling the bonding temperature includes controlling the bonding temperature based at least in part on the difference in solubility parameter between the polymeric substrate material and the bonding solvent. 